1. Field of the Invention
This invention relates to an improved process for producing the optically pure C.sub.10 -C.sub.18 fragment of FK-506 useful as an intermediate in synthesizing the FK-506 immunosuppressant and derivatives thereof.
2. Brief Disclosures in the Art
The novel 23-membered tricyclo-macrolide FK-506 very recently isolated and characterized by Tanaka, Kuroda, and co-workers, see JACS, 109, pp. 5031, 1987, and EPO Publication No. 0184162, has been shown to possess exceptional immunosuppressive activity. The potential usefulness of such an agent in bone marrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate an effort towards the total synthesis of FK-506.
A highly diastereoselective synthesis of a Protected C.10-C.18 subunit, in its correct absolute configuration, has already been achieved as reported by D. Askin, R. P. Volante, R. A. Reamer, K. M. Ryan and I. Shinkai in Tetrahedron Letters. 1988, 29, pp. 277-280. See also: (a) Villalobos, A.; Danishefsky, S. J., J. Org. Chem., 1989, 54. pp. 15-16; (b) Schreiber, S. L.; Sammakia, T.; Uehling, D. E., J. Org. Chem., 1989, 54, pp. 16-17.
Further, a general synthesis of the C.sub.10 -C.sub.18 fragment is disclosed in Ser. No. 149,464, now abandoned filed Jan. 28, 1988, by D. Askin, K. M. Ryan, R. P. Volante and I. Shinkai (assigned to Merck & Co. Inc. , hereby incorporated, by reference.
The novel 23-membered tricyclo-macrolide FK-506 very recently isolated and characterized by Tanaka, Kuroda, and co-workers, see JACS, 109, pp. 5031, 1987, and EPO Publication No. 0184162, has been shown to possess exceptional immunosuppressive activity. The potential usefulness of such an agent in bone marrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate an effort towards the total syntehsis of FK-506. A highly diastereoselective synthesis of a protected C.10-C.18 subunit 1, in its correct absolute configuration, i.e., ##STR1## has already been achieved as reported by D. Askin R. P. Volante, R. A. Reamer, KM. M. Ryan and I. Shinkai in Tetrahedron Letters, 1988, in press.
However, what is needed is an overall general syntehsis utilizing readily available starting materials which would allow the synthesis of all the possible diastereoisomers of the C.sub.1 -C.sub.18 fragment of FK-506, some of which may exhibit greater immunosuppressant activity than the naturally occurring form itself.
However, this process, Published by D. Askin et al., Tetrahedron Letters, 1988, pages 277 and 4245, requires 17 consecutive chemical steps to produce the key intermediate IX. Further, the method requires 3 isomer separations, which are both technically demanding and expensive. In addition, the method requires the use of an expensive reagent (R-pyrrolidinemethanol) in a 5-fold excess at an early stage of the process, also significantly increasing the overall expense.
What is constantly being searched for in the art are newer, more economical methods to produce FK-506 and its derivatives via an inexpensive and convenient total synthesis scheme.